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FOXP2 (Forkhead Box P2)


Chromosome
      The FOXP2 gene in humans is found on chromosome 7, on the base pairs 114,086,309 to 114,693,771. This is also interesting because 7q31 has been found to be associated with autism, and the fact that the FOXP2 gene is so close to 7q31 is believed to point to the possibility that FOXP2 also affects similar attributes such as speech and language.
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Discovery
      In 1990 a family, referred to as "KE," was found in which 16 members of the family, spanning three generations, presented severe developmental speech impairments. However, they all had normal intelligence and hearing, two common causes for developmental speech impairment. It was also found that inheritance of this trait was heterozygous dominant, meaning that it only took one version of the mutated gene for a person to present symptoms. After many studies on this family, it was found that the affected members had difficulty with grammar, specifically with syntactic rules. They also presented difficulty articulating speech, and on average, had lower IQ scores than the members of the family that did not have a mutation in the FOXP2 gene.
Gene Expression
      Having even one version of the mutated FOXP2 gene can affect almost any aspect of language and speech, the specific disorder being speech-language disorder 1 (SPCH1). This is due to irregular development of areas of the brain that greatly affect speech and language. FOXP2 also affects the muscles that are needed to make the particular facial movements that allow for people to pronounce words, making it so that people that are affected by FOXP2 have slurred speech. FOXP2 is considered to be what allows humans to speak.
      The FOXP2 gene is one of a family of genes known as the FOX forkhead family.
Protein
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      The FOXP2 gene encodes for an important regulatory protein that regulates for many other genes as well. FOXP2 is a transcription factor, meaning that the protein that it encodes for is regulatory, it will only act in a certain way under certain conditions. Although some pathways in the FOXP2 gene are well studied, there is very little research on the proteins that FOXP2 interacts with. There is current research looking into these interactions, especially how FOXP2 interacts with the FOXP1 protein, which is also related to developmental disorders such as autism. 
      The FOXP2 protein domain can be in the form of a dimer, meaning that two of the FOXP2 proteins will bind to each other. However, for the entire FOX family this domain dimer is often swapped, meaning that the two proteins will not be symmetrical because pieces of one protein can swap with pieces of the other. This ability to swap part of the protein is unique to the FOX family, and is thought to be one of the reasons that the FOX genes act the way that they do. This swapping in the protein can be seen in the images of the protein structure. It is clear in these images that there are two places to bind to DNA (the double helix structures in the images).

Gene Interaction
     Very little is known about the gene interactions of FOXP2. FOXP2 is a transcription factor and its correlation with speech was discovered by the speech disorder in its absence. FOXP2 is the only identified gene that causes speech disorders. Although scientists know that FOXP2 has transcriptional targets in the brain and the neural system, they are as of yet unsure as to what specifically those targets are. People with FOXP2 mutations tend to have abnormalities in the Basal Ganglia and interior frontal cortex parts of the brain. However, other research shows that FOXP2 may have interactions in the lungs, like the similar FOXP2 gene in mice. 
Evolutionary History

      The FOXP2 gene is present in other species besides humans but has some key differences that may give humans the ability to speak. Humans' FOXP2 protein has three amino acids different from mice's protein and two amino acids different from primates such as chimpanzees and gorillas. The human evolutionary line diverged from the lineage of the mouse approximately 70 million years ago. Humans and chimpanzees diverged approximately 5 million years ago. In the 65 million years between mice and the human chimp common ancestor, only one mutation occurred. However, in the last 5 million years, two mutations have occurred between humans and chimpanzees. It is therefore extremely likely that those two mutations between humans and primates are essential to our ability to speak and have been selected for over the more recent years of human evolution.
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      The grey bars represent amino acid changes and black bars represent nucleotide changes. This diagram shows how humans have a version of FOXP2 with two different amino acids which most likely have been positively selected for because of their large effect on the ability to speak.
Importance
      A complex language is not only a clear difference between humans and all other animals but also an adaptation that gives humans a significant advantage over other species. Complex communication between humans led to the development of culture and much faster and more accurate spread of successful memes.  While there are likely many genes that contribute to human speech, FOXP2 is one of the first discovered and one that's version in humans seems to have a clear difference from FOXP2 in primates. As chimpanzees share 96 percent of their genome with humans, many scientists wonder how humans came to rule the Earth instead of chimpanzees or another primate. Although there is much left to be discovered, significant evidence suggests that the two amino acid change in the FOXP2 gene could have made the difference.
Primers Used in PCR Lab in Class

      Forward Primer: 5-TGTGGGTTACCTGCTTTGGT-3
      Reverse Primer: 5-ATTTGTGGCTCAGCTGCCTA-3

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      Both of these primers are exactly 20 base pairs long and have a GC% (the proportion of G's and C's in the primer) of exactly 50%. However, the Forward Primer temperature is 59.45 as opposed to the Reverse Primer temperature of 59.67. The expected piece of DNA using these two primers is 509 base pairs long. 
      To the left is an image of the gel after doing PCR with these primers. Both columns 1 and 3 are the results after gel-electrophoresis using these primers. Column 2 is the ladder, meaning that it shows how far down different lengths of DNA should be on the gel according to the number of base pairs. The brightest band on the ladder is the mark for where a 500 base pair piece of DNA should end up, and since using this these primers we expect the length of DNA to be 509 base pairs long, we expect that the clearest band for our PCR to be in line with the bright line on the ladder.
      The PCR in column 1 was not as successful as the PCR in column 3. This is clear because there is a single bright band in column 3 whereas in column one there are a couple bands and none of them are particularly brighter than the others. However, in both cases the brightest bands are below the level of the 500 base pair band on the ladder. This means that the DNA that was actually amplified through PCR was slightly shorter than expected. This difference in DNA length could be due to a longer an intron that was maybe included in the approximation for the length of the piece of DNA but that was not actually present during PCR. Whatever the reason, this difference in length is very apparent and should be noted.
Other Possible Primers to Use for FOXP2:

      FOXP2-1
            Forward Primer:  5 -TGGGAGATCAAGTGGTGACA-3 
            Reverse Primer:  5 -GCTGCTCTTTTGCTTGCTTT-3

      FOXP2-2
            Forward Primer: 5 -AATGTGGGAGCCATACGAAG-3
            Reverse Primer:  5 -CCACTGGAGGCGTTATTGAT-3

      FOXP2-3
            Forward Primer:  5 -CAACAGCAGCAGCAGCAAC-3
            Reverse Primer: 5 -GAGGCCCCAGTCTCCTCA-3

      FOXP2-4
            Forward Primer: 5 -GAGGCCCCAGTCTCCTCA-3
            Reverse Primer: 5 -GAGGCCCCAGTCTCCTCA-3
Picture
This image shows the steps involved in PCR amplification. After this, the copied target DNA goes into gel electrophoresis. 

Bibliography
Bernhard, Martina. "Protein Networks in Speech and Language." Max Planck 
     Institute of Psycholinguistics. Max Planck Gesellschaft, 28 Nov. 2013. Web. 
     5 May 2014. <http://www.mpi.nl/departments/language-and-genetics/ 
     projects/protein-networks-in-speech-and-language>.

"Chemical Steps Involved in PCR." Priory Medical Journals. Priory Lodge 
     Education, 1999. Web. 21 May 2014. <http://www.priory.com/cmol/ 
     TBMultid.htm>. 

Chuey, Dan. "Forkhead Box P2." Biology at Davidson. Davidson College, 2003. Web. 
     5 May 2014. <http://www.bio.davidson.edu/courses/genomics/2003/cheuy/ 
     FOXP2.html>. 

Enard, Wolfgang. "Molecular Evolution of FOXP2, a Gene Involved in Speech and 
     Language." Evolutionary Biology. Nature Publishing Group, 22 Aug. 2002. 
     Web. 5 May 2014. <http://www.evolution.unibas.ch/teaching/molec_evol/doc/ 
     Enard_et_al_2002.pdf>. 

Ferland, Russell J., et al. "Characterization of Foxp2 and Foxp1 mRNA and 
     Protein in the Developing and Mature Brain." J Comp Neurol 460.2 (2003): 
     266-79. PubMed. Web. 25 Apr. 2014. <http://www.ncbi.nlm.nih.gov/pubmed/ 
     12687690>. 

"FOXP2." Genetics Home Reference. N.p., 24 Apr. 2014. Web. 25 Apr. 2014. 
     <http://ghr.nlm.nih.gov/gene/FOXP2>. 

Gerritsen, Vivienne Baillie. "Talking Heads." Protein Spotlight. N.p., Oct. 
     2004. Web. 7 May 2014. <http://web.expasy.org/spotlight/back_issues/ 
     051/>. 

Kniffin, Cassandra L. "Speech-Language Disorder 1; SPCH1." Online Mendelian 
     Inheritance in Man. N.p., 27 Oct. 1997. Web. 21 Apr. 2014. 
     <http://omim.org/entry/602081?search=foxp2&highlight=foxp2>.

Marcus, Gary F., and Simon E. Fisher. "FOXP2 in Focus: What Can Genes Tell Us 
     about Speech and Language?" TRENDS in Cognitive Sciences 7.6 (2003): 
     257-62. MIT. Web. 21 Apr. 2014. <http://www.ai.mit.edu/projects/dm/ 
     foxp2.pdf>. 

Padovani, Alessandro, et al. "The Speech And Language FOXP2 Gene Modulates 
     The Phenotype Of Frontotemporal Lobar Degeneration." Journal Of Alzheimer's 
     Disease 22.3 (2010): 923-931. Academic Search Premier. Web. 25 Apr. 2014.

Primer-BLAST. N.p., n.d. Web. 5 May 2014. <http://www.ncbi.nlm.nih.gov/tools/ 
     primer-blast/ 
     primertool.cgi?ctg_time=1399321244&job_key=JzzLtfK_W5tgI2QvBQFWUR4sZEANM3lF>. 

Shu, Weiguo, et al. "Altered Ultrasonic Vocalization in Mice with a Disruption 
     in the FOXP2 Gene." Proc Natl Acad Sci USA 102.27 (2005): 9643-48. PMC. 
     Web. 21 May 2014. <http://www.ncbi.nlm.nih.gov/pmc/articles/ 
     PMC1160518/>. 

Stroud, J. C., et al. "Structure of the Forkhead Domain of FOXP2 Bound to DNA." 
     Structure 14.1 (2006): 159-66. Pub Med. Web. 20 May 2014. 
     <http://www.ncbi.nlm.nih.gov/pubmed/16407075>. 

Transcription Factor-DNA,  
     Molecular Model.Photography. Encyclopædia Britannica ImageQuest.
     Web. 21 Apr 2014.
     http://quest.eb.com/images/132_1223768
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